The recent diphtheria epidemic in the former Soviet Union has resulted in a heightened agent of diphtheria. With the exception of diphtheria toxin, little information is available concerning the pathogenesis of this organism with respect to its ability to invade, colonize and survive within the human host. The acquisition of iron is an important virulence determinant for many bacterial pathogens, and numerous virulence factors including diphtheria toxin are regulated by iron. The hmuO gene is required for the utilization of heme and hemoglobin as iron sources by C. diphtheriae. The product of hmuO has homology to eukaryotic heme oxygenases which are involved in the degradation of heme and release of iron. Current studies have focused on 1) understanding the molecular mechanisms by which the hmuO gene is regulated, 2) purification and characterization of the activity of the HmuO protein and 3) the characterization of a newly identified operon in C. diphtheriae that is required for heme transport. Transcription from the hmuO promoter has been shown to be under dual regulation in which expression is positively regulated by a heme source, such as heme or hemoglobin, and negatively regulated by the diphtheria toxin repressor protein (DtxR) and iron. Two genes from C. diphtheriae capable of activating the hmuO promoter have been recently cloned and sequenced. The amino acid sequence of the putative proteins encoded by these genes shares significant homology with a family of related activator proteins that are associated with two-component signal transduction systems. At least three genes involved in heme transport have also been cloned and sequenced. The proteins encoded by theses genes are homologous to ABC (ATP-binding cassette) transport systems and show the highest homology to a family of proteins in gram negative bacteria that are required for the transport of heme. The HmuO protein was recently purified, and measurement of heme oxygenase activity in an in vitro assay system indicated that the C. diphtheriae HmuO protein possessed a heme oxygensase activity that was virtually identical to that observed by various eukaryotic heme oxygenase enzymes.